Project summary. Microorganisms that cause human disease must be able to respond to stresses encountered in the host environment. These cellular responses include morphogenic changes, or modifications of the cytoskeleton that determine cell size, shape, and volume. The long-term goals of this proposal are to define the molecular events that allow microbial pathogens to regulate these processes and adapt to the hostile environment of the infected host. The human fungal pathogen Cryptococcus neoformans is an important model system for understanding basic issues in microbial pathogenesis. In response to stresses encountered during a host-parasite interaction, C. neoformans displays reproducible alterations in its cytoskeleton. These morphogenic responses allow the cell to adapt to elevated temperatures and other host-specific conditions. The Ras1 protein controls the intracellular signaling events that direct many of these adaptive cellular responses. The experiments in this proposal will define the ways in which C. neoformans uses Ras1 and a cascading series of protein interactions to survive and grow within the host. First, unique components of the Ras1 morphogenesis pathways will be studied to determine how these proteins specifically direct morphogenesis and growth at 37C. Second, a compendium of microarray data will be created to more fully define those proteins that function in the various arms of the Ras1 signaling pathways. Finally, Ras protein localization within the cell will be studied to define its role in determining Ras signaling specificity in a microbial pathogen. Relevance:. Defining the ways in which microorganisms interact with their host will result in better understanding and treatment of infectious diseases. The studies in this proposal will characterize the ways in which Ras proteins allow microorganisms to respond to the stresses encountered within the infected host. Manipulation of Ras and its related proteins directly affects microbial survival and offers a unique option for the development of new anti-infective therapies. NARRATIVE : Defining the ways in which microorganisms interact with their host will result in better understanding and treatment of infectious diseases. The studies in this proposal will characterize the ways in which Ras proteins allow microorganisms to respond to the stresses encountered within the infected host. Manipulation of Ras and its related proteins directly affects microbial survival and offers a unique option for the development of new anti-infective therapies.